Angiogenesis, the sprouting of new capillaries from existing vessels, is an important process that governs embryonic development, reproduction, wound healing, and a spectrum of diseases including cancer. Recent studies have shown that angiogenesis is essential for the growth of solid tumors beyond a certain size, and intervention with tumor angiogenesis can dramatically restrict tumor development. Thus, understanding the control of angiogenesis has emerged as a challenge of fundamental biological significance, and may lead to therapeutic possibilities for the treatment of cancer. Through the characterization of growth factor induced genes, a new angiogenic inducer has been recently discovered. Cyr61, encoded by a growth factor inducible, immediate early gene, promotes endothelial cell adhesion, enhances growth factor induced DNA synthesis in endothelial cells, stimulates directed capillary endothelial cell migration in vitro, and induces neovascularization in vivo. Cyr61 is a novel ligand of the integrin alphavbeta3, known to be important for angiogenesis. Furthermore, expression of cyr61 in a tumor cell line that does not normally express it enhances the size and vascularization of tumors that develop from these cells. Cyr61 is a member of a conserved protein family, suggesting that other members of this family may also regulate antiogenesis. Together, these findings suggest that Cyr61 and related proteins are novel angiogenic regulators whose activities and functions merit further investigation. The activities and functions of Cyr61 and related proteins are examined in this proposal through several approaches. First, the angiogenic activities of these proteins will be determined and the role of integrin alphavbeta3 in their actions will be assessed. Second, the structure and function relationships of Cyr61 will be analyzed. Third, the role of Cyr61 in tumor growth and metastasis will be evaluated, and intervention of Cyr61 activities will be explored as a means of restricting tumor growth.